System and method for freeze-drying and packaging

ABSTRACT

A system and method for protecting biological or other material from contamination through the steps of filling, freeze-drying, packaging, storing and use are disclosed. A system can include a flexible container, a membrane configured to transmit air or solvent vapor out of the flexible container, and a membrane frame supporting the membrane and engaged with at least one column member. The at least one column member can be configured to maintain the membrane and the membrane frame a spaced distance from one or more contents received within the flexible container. Upon application of a downward force, the at least one column member can assume a collapsed configuration. A method can include inserting a biological material, for example, into a flexible container, freeze-drying the biological material, moving the freeze-dried biological material to a portion of the flexible container that includes at least one port, and sealing the biological material within the portion.

CLAIM OF PRIORITY

This non-provisional patent application is a divisional application ofU.S. non-provisional patent application Ser. No. 15/399,643, issued asU.S. Pat. No. 10,377,520, entitled “SYSTEM AND METHOD FOR FREEZE-DRYINGAND PACKAGING” and filed on Jan. 5, 2017, which is a divisionalapplication of U.S. non-provisional patent application Ser. No.14/553,722, issued as U.S. Pat. No. 9,561,893, entitled “SYSTEM ANDMETHOD FOR FREEZE-DRYING AND PACKAGING” and filed on Nov. 25, 2014,which claims the benefit of priority under 35 U.S.C. § 119(e) to U.S.provisional patent application Ser. No. 61/912,281, entitled “SYSTEM ANDMETHOD FOR FREEZE-DRYING AND PACKAGING” and filed on Dec. 5, 2013, eachof which is herein incorporated by reference in its entirety.

TECHNICAL FIELD

This patent document pertains to a system and method for, among otherthings, freeze-drying and packaging a material under aseptic orpathogen-reduced conditions.

BACKGROUND

Dry storage can increase the shelf life and convenience of biologicalmaterial and its use. Lyophilization is a process for dryingheat-sensitive substances, such as biological materials, by freezing thesubstances and then subliming the ice or other frozen solvent in a highvacuum.

It can be necessary to keep biological material free frommicro-organisms and other contaminants to avoid decomposition of thematerial and to prevent possible infections when the material is used.Biological material can be exposed to contaminants during transportationto and from a freeze-dryer. As a result, the operating area in whichfreeze-drying is carried out can undergo sterilization treatment tominimize exposure of the biological material to contaminants. This addsto the labor and costs associated with freeze-drying.

Many freeze-drying processes involve placing open containers ofbiological material in the freeze-dryer. The containers remain open tothe environment until the freeze-drying process is complete to allow apath for solvent vapor to be removed from the biological material. Thispractice exposes the biological material to potential contaminationduring the freeze-drying process. To minimize the opportunity forcontamination during the freeze-drying process, the freeze-dryingequipment can be sterilized using steam or chemicals before loading eachnew batch of biological material to be processed. This, too, adds to thelabor and costs associated with freeze-drying.

Moreover, using existing systems and methods, freeze-dried biologicalmaterial needs to be repackaged after being dried. This repackagingpresents another opportunity to introduce contaminants into thebiological material and further adds to the labor and costs associatedwith freeze-drying.

OVERVIEW

The present inventors recognize, among other things, that a need existsfor a system and method that addresses the concerns of materialcontamination by freeze-drying equipment, the area surrounding thefreeze-drying equipment, and the repackaging of freeze-dried product.The inventors recognize that biological material, such as blood plasma,is associated with a risk of contamination anytime it is exposed to theenvironment. The inventors also recognize that the system and methodshould be economical and practical on a production scale.

The present subject matter provides a system and method for protectingbiological material, for example, from contamination through the stepsof filling, freeze-drying, packaging, storing and use. A system caninclude a flexible container, a membrane configured to transmit air orsolvent vapor out of the flexible container, and a membrane framesupporting the membrane and engaged with at least one column member. Theat least one column member can be configured to maintain the membraneand the membrane frame a spaced distance from one or more contentsreceivable within the flexible container. Upon application of a downwardforce, the at least one column member can assume a collapsedconfiguration. A method can include inserting a biological material, forexample, into a flexible container, freeze-drying the biologicalmaterial, moving the freeze-dried biological material to a portion ofthe flexible container that includes at least one port, and sealing thebiological material within the portion.

To further illustrate the system and method disclosed herein, anon-limiting list of examples is provided here:

In Example 1, a system can comprise a flexible container, a membrane,and a membrane frame engaged with at least one column member. Theflexible container can be defined by a height of a first dimension and awidth of a second dimension. The height can separate the flexiblecontainer into a first portion and a second portion at an intermediatelocation (e.g., the flexible container's midline). The membrane can belocated within the first portion and can be configured to transmit airor solvent vapor out of, and resist liquid and contaminant passage into,the flexible container. The membrane frame can be coupled to both themembrane around its perimeter and a portion of the flexible container.The at least one column member can support the membrane and the membraneframe a spaced distance from one or more contents receivable within theflexible container.

In Example 2, the system of Example 1 can optionally be configured suchthat the at least one column member includes a plurality of columnmembers. Each column member can be configured to change shape orposition, relative to the membrane frame, upon application of a downwardforce to the membrane frame.

In Example 3, the system of Example 2 can optionally be configured suchthat each of the plurality of column members include at least one endengaged with the membrane frame and at least one end in contact with asurface of the flexible container.

In Example 4, the system of any one or any combination of Examples 2 or3 can optionally be configured such that each of the plurality of columnmembers defines a U-shape. The curvature of the U-shape can be engagedwith the membrane frame.

In Example 5, the system of any one or any combination of Examples 1-4is optionally configured such that the at least one column member isintegral with the membrane frame.

In Example 6, the system of any one or any combination of Examples 1-5can optionally be configured such that front and back sides of theflexible container are sealed to one another along an outer perimeter.

In Example 7, the system of Example 6 can optionally be configured suchthat a widthwise cross-section of the flexible container at theintermediate location defines an ellipsoid (or tear drop) shape.

In Example 8, the system of any one or any combination of Examples 1-7can optionally be configured such that the flexible container includes aheat-sealable material.

In Example 9, the system of any one or any combination of Examples 1-8can optionally be configured such that the membrane includes a materialselected from a porous polymer, a woven polymeric fabric, a non-wovenpolymeric fabric, glass fiber or cellulose.

In Example 10, the system of Example 9 can optionally be configured suchthat the membrane includes a porous polymer material in the form ofpolytetrafluoroethylene.

In Example 11, the system of any one or any combination of Examples 1-10can optionally further comprise a material entry port coupled to theflexible container within the first portion.

In Example 12, the system of Example 11 can optionally be configuredsuch that the material entry port includes a tube extending from a firstend, coupled to the flexible container, to a second end, couplable to amaterial source.

In Example 13, the system of any one or any combination of Examples 1-12can optionally further comprise a reconstitution port coupled to anouter perimeter of the second portion of the flexible container and influid communication with an interior of the flexible container.

In Example 14, the system of any one or any combination of Examples 1-13can optionally further comprise an application port coupled to an outerperimeter of the second portion of the flexible container and in fluidcommunication with an interior of the flexible container.

In Example 15, the system of any one or any combination of Examples 1-14can optionally further comprise a single donor quantity of biologicalmaterial within the flexible container.

In Example 16, the system of Example 15 can optionally be configuredsuch that the single donor quantity of biological material includesblood plasma.

In Example 17, a method can comprise inserting a material into aflexible container including a membrane, freeze-drying the material,moving the freeze-dried material to a portion of the flexible containerspaced from the membrane, and sealing the material within the portion ofthe flexible container. The membrane can be incorporated into a firstcontainer side and can be spaced from a second container side by amembrane frame and at least one column member.

In Example 18, the method of Example 17 can optionally further compriseapplying a force to the membrane frame in a direction of the secondcontainer side.

In Example 19, the method of Example 18 can optionally be configuredsuch that applying the force to the membrane frame in the direction ofthe second container side includes causing the at least one column tocollapse relative to the membrane frame.

In Example 20, the method of any one or any combination of Examples17-19 can optionally be configured such that sealing the material withinthe portion of the flexible container spaced from the membrane includesfluidly coupling a reconstitution port and the material.

In Example 21, the method of any one or any combination of Examples17-20 can optionally be configured such that sealing the material withinthe portion of the flexible container spaced from the membrane includesfluidly coupling an application port and the material.

In Example 22, the method of any one or any combination of Examples17-21 can optionally be configured such that sealing the material withinthe portion of the flexible container spaced from the membrane includessealing across a width of the flexible container at a location in whichthe flexible container has capacity to receive at least 200 mL(milliliter) of a reconstitution liquid.

In Example 23, the method of Example 22 can optionally further comprisecutting through a formed seal and discarding a portion of the flexiblecontainer including the membrane, the membrane frame, and the least onecolumn member.

In Example 24, the method of Example 23 can optionally further compriseforming a hang lumen through the remaining portion of the formed sealand cleaning the formed seal of material residue.

In Example 25, the method of any one or any combination of Examples17-24 can optionally be configured such that freeze-drying the materialin the flexible container includes freeze-drying blood plasma from asingle donor or a pooling of donors.

In Example 26, the method of any one or any combination of Examples17-25 can optionally further comprise labeling the portion of theflexible container in which the material is sealed.

In Example 27, the system or method of any one or any combination ofExamples 1-26 can optionally be configured such that all features,components, operations, or other options recited are available to use orselect from.

These and other examples and features of the present system or methodwill be set forth, at least in part, in the following DetailedDescription. This Overview is intended to provide non-limiting examplesof the present subject matter—it is not intended to provide an exclusiveor exhaustive explanation. The Detailed Description below is included toprovide further information about the present system or method.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, like numerals can be used to describe similar featuresand components throughout the several views. The drawings illustrategenerally, by way of example, but not by way of limitation, variousembodiments discussed in the present patent document.

FIG. 1 illustrates a front elevational view of a system, as constructedin accordance with at least one embodiment.

FIG. 2 illustrates an elevational view of a top portion of a system, asconstructed in accordance with at least one embodiment.

FIG. 3 illustrates a side view of a top portion of a system, asconstructed in accordance with at least one embodiment.

FIG. 4 illustrates a cross-sectional view of a system such as across-section taken along line 4-4 of FIG. 1.

FIG. 5 illustrates a cross-sectional view of the system, such as across-section taken along line 5-5 of FIG. 1.

FIG. 6 illustrates a cross-sectional view of a membrane, a membraneframe and a flexible container, such as a cross-section taken along line6-6 of FIG. 5.

FIG. 7 illustrates an elevational view of a top portion of a system, asconstructed in accordance with at least one embodiment.

FIG. 8 illustrates a front elevational view of a membrane, a membraneframe, and at least one column member in a relaxed configuration, asconstructed in accordance with at least one embodiment.

FIGS. 9-11 illustrate sequential perspective views of a membrane, amembrane frame, and at least one column member subjected to a force F ina downward direction, as constructed in accordance with at least oneembodiment.

FIG. 12 illustrates an elevational view of a bottom portion of a system,as constructed in accordance with at least one embodiment.

FIG. 13 illustrates a schematic view of reconstituting a freeze-driedmaterial, as constructed in accordance with at least one embodiment.

FIG. 14 illustrates a schematic view of applying a reconstitutedmaterial to a patient, as constructed in accordance with at least oneembodiment.

FIG. 15 illustrates a method of filling a flexible container with amaterial freeze-drying the material and packaging the material for lateruse, as constructed in accordance with at least one embodiment.

The drawing figures are not necessarily to scale. Certain features andcomponents may be shown exaggerated in scale or in schematic form andsome details may not be shown in the interest of clarity andconciseness.

DETAILED DESCRIPTION

The present subject matter includes a method that protects material fromcontamination through the steps of filling, freeze-drying, packaging,storing and use. The method can include inserting a material into aflexible container, freeze-drying the material, moving the freeze-driedmaterial to a portion of the flexible container that includes at leastone port, and sealing the material within the portion. The method can beperformed using a system as shown in the drawings and described herein.The system provides a practical, durable freeze-drying container andmembrane that provide sufficient solvent vapor flow, resistance tobreakage, wetting and abrasion, and aseptic barrier properties.

FIG. 1 illustrates a front elevational view of a system 100 configuredto house a material, such as blood plasma from a single donor. Thesystem can include a flexible container 102, a membrane 104, and amembrane frame 106 engaged with at least one column member 108 (shown inphantom).

The flexible container 102 can be used in a freeze-drying process.Biological material, for example, to be freeze-dried can be receivedwithin the flexible container 102 prior to lyophilization. The flexiblecontainer 102 can include a front side 110 and a back side 112, and candefine a height H of a first dimension and a width W of a seconddimension. The second dimension can be smaller than the first dimension.The terms “front” and “back,” as used herein, refer to opposing walls ofthe flexible container 102 when it is placed on a freeze-dryer shelfwith the membrane 104 facing upward. The height H can have anintermediate location (e.g., a midline) separating the flexiblecontainer into a first portion 114 and a second portion 116. In anexample, the height H can be 6-18 inches, such as about 12 inches, andthe width W can be 3-9 inches, such as about 6 inches.

The flexible container 102 can include a sealable material made of aninert medical grade plastic material, such as polyvinyl chloride (PVC),polypropylene or high density polypropylene, which is designed to resisttearing and puncturing that can be encountered in normal handling. Thesealable material can be selected to be transparent to allow visualinspection of the biological material within the flexible container 102and can be available in a variety of sizes, such as about 10 mL up toabout 10 L. The front 110 and back 112 sides of the flexible container102 can be heat-sealed or, alternatively, ultrasonically orradio-frequency (RF) welded to one another along an outer perimeter.This thermal scaling can be performed by Dravon Medical of Clackamas,Oreg.

The membrane 104 can be located within the first portion 114 of theflexible container 102 and can have a height of 1-3 inches, such asabout 2 inches, and a width of 2-4 inches, such as about 3 inches. Themembrane 104 can be configured to transmit air or solvent vapor out of,and resist liquid and contaminant passage into, the flexible container102. The membrane's material can be selected for its combination of highaseptic barrier properties, high resistance to penetration and wettingby liquid water, and low resistance to solvent vapor flow. In anexample, the material of the membrane 104 can includepolytetrafluoroethylene (PTFE), which is available from PorexCorporation of Fairburn, Ga. The membrane 104 can be separate from, butattachable to, the front side 110 of the flexible container 102 by wayof the membrane frame 106. In such examples, the membrane's materialshould have the ability to seal reliably to a material of the membraneframe 106.

The membrane frame 106 can be coupled to the membrane 104 around itsperimeter and the front side 110 of the flexible container 102. Themembrane frame 106 can provide strength and support to the membrane 104.The membrane frame 106 can be engaged with at least one collapsiblecolumn member 108 to prevent the membrane 104 from contacting biologicalmaterial, for example, located within the flexible container 102, suchas during the lyophilization process. The at least one column member 108can be configured to support the membrane 104 and the membrane frame 106a spaced distance from the back side 112 of the flexible container 102.In an example, the membrane frame 106 can be manufactured by TaurisManufacturing of Minneapolis, Minn.

The system 100 can further include a plurality of ports to allow for theintroduction or withdrawal of a material or substance into or out of theflexible container 102. A material entry port 118 can be coupled to thefirst portion 114 of the flexible container 102 and can be used toinsert the biological material and, optionally, other materials withinthe container. In an example, one or more pH-adjusting substances can beinserted into the flexible container 102 and combined with thebiological material to affect a predetermined pH value range in areconstituted material solution. In an example, the material entry portcan include a tube extending from a first end 120, coupled to the firstside 110 of the flexible container 102, to a second end 122, couplableto a biological material source. A reconstitution port 124 and anapplication port 126 can be coupled to an outer perimeter of the secondportion 116 of the flexible container 102 and can be in fluidcommunication with an interior of the container. These ports 124, 126can allow a user to introduce a reconstitution (or rehydration) solutioninto the flexible container 102 and administer a rehydrated product(e.g., reconstituted biological material) to a patient, respectively, inan aseptic manner.

The system 100, including the flexible container 102, the membrane 104,the membrane frame 106 and the at least one column member 108, can besterilized prior to use.

FIGS. 2 and 3 illustrate elevational and side views, respectively, of atop portion 214, 314 of a system 200, 300. Each system 200, 300 caninclude a flexible container 202, 302 having a front side 210, 310 and aback side 212, 312, a membrane 204, 304, a membrane frame 206, 306 andat least one column member 208, 308.

Containers without sidewalls can include contents that contact amembrane resulting in the material freezing against the membrane. Thematerial can then dry against and plug up the membrane resulting inreduction of a lyophilization rate and a reduced usefulness of thesystem. As such, it is important to prevent the membrane from contactingcontainer contents (e.g., biological material). Advantageously, the atleast one column member 208, 308 can maintain one or more of the frontside 210, 310 of the flexible container 202, 302, the membrane 204, 304,and the membrane frame 206, 306 above any contents duringlyophilization. The at least one column member 208, 308 can besufficiently stiff to support the front side 210, 310, the membrane 204,304, and the membrane frame 206, 306 above the contents, yetsufficiently deformable or pliable to collapse subsequent tolyophilization, as sequentially illustrated in FIGS. 9-11. The at leastone column member 208, 308 can have various linear or non-linearconfigurations, including a bent leg shape, a helical spring shape or atubular shape.

FIGS. 4 and 5 illustrate cross-sectional views of a system 400, 500,such as cross-sections taken along lines 4-4 and 5-5 of FIG. 1,respectively. As partially shown in FIG. 4, a widthwise cross-section ofthe flexible container 402 can assume an ellipsoid shape in the absenceof sidewalls. Flexible containers without sidewalls can be efficientlyand economically manufactured using a single, outer perimeter sealingstep. With the addition of at least one column member 408, 508, amembrane 404, 504 and a membrane frame 406, 506 can be supported aboveany material contents, as shown in FIGS. 4 and 5.

FIG. 6 illustrates a cross-sectional view of a system 600, such as across-section taken along line 6-6 of FIG. 4. The system 600 can includea front side 610 of a flexible container 602, a membrane 604 and amembrane frame 606. To assemble these portions of the system 600, themembrane frame 606 can be laid on top of the membrane 604, and the frontside 610 of the flexible container 602 can be laid on top of both themembrane 604 and the membrane frame 606. The three layers can then beadhesive coupled or bonded with a heat-sealer, an ultrasonic welder, oran RF welder to bond a bottom surface 628 of the membrane frame 606 to atop surface 630 of the membrane and a top surface 632 of the membraneframe 606 to a bottom surface 634 of the front side 610 of the flexiblecontainer 602. For aseptic reasons, it can be important that the sealsbetween the membrane 604, the membrane frame 606 and the flexiblecontainer 602 are fluid and vapor tight.

The system 600 can include one or more magnetic members or one or morehook members coupled to or integrated with the flexible container 602,the membrane 604 or the membrane frame 606. The magnetic or hook memberscan interact with an external magnetic member or an external support tomaintain the membrane 604 above any material contents within theflexible container. The one or more magnetic or hook members can be usedalone or in conjunction with the at least one column member describedelsewhere in this patent document.

FIG. 7 illustrates an elevational view of a top portion 714 of a system700. The system 700 can include a front side 710 of a flexible container702, a membrane 704, and a membrane frame 706. The front side 710 of theflexible container 702 and the membrane 704 can be supported along theirperipheries by the stiffer membrane frame 706. The membrane 704 can besized such that its outer periphery is larger than an inner periphery736 of the membrane frame 706 and smaller than, or equal to, an outerperiphery 738 of the membrane frame 706. A void in the front side 710 ofthe flexible container 702 can have a periphery that is smaller than theouter periphery 738 of the membrane frame 706 and larger than, or equalto, the inner periphery 736 of the membrane frame 706.

During lyophilization, solvent vapor can pass out of the flexiblecontainer 702 through the membrane 704 in a variety of directions, suchas one or more of D₁, D₂, D₃, and D₄. Particulate biological material,for example, can be retained within the flexible container 702 andcontamination from the container's surroundings can be excluded by theaseptic barrier properties of the membrane 704. The membrane 704 can bemade of any vent material that is solvent vapor permeable and thatprovides effective resistance to bacterial penetration. Aseptic papers,woven or non-woven polymeric fabrics, such as spun-bonded polyolefin,porous polymer membranes, such as PTFE and ePTFE, glass fiber,nitrocellulose, mixed cellulose esters, polyvinylidene fluoride (PVDF),polyethersulfone, polycarbonate, nylon, polypropylene, and PVC areexamples. PTFE can be a preferred membrane material based on itscombination of hydrophobicity and solvent vapor flow for a given nominalpore size.

Optionally, a removable cover 740 (shown in phantom) can be added to anupward-facing surface of the membrane 704. The removable cover 740 canprotect the membrane 704 during any processing before lyophilization.The removable cover 740 can include a tab that extends beyond the inner736 or outer 738 peripheries of the membrane frame 706 to allow a userto grasp and remove the cover to expose the membrane 704.

FIG. 8 illustrates a front elevational view of a membrane 804, amembrane frame 806 and at least one column member 808 in a relaxedconfiguration. The at least one column member 808 can be sized, shapedand positioned to support the membrane 804 and the membrane frame 806above any contents (e.g., biological material) within a flexiblecontainer. The at least one column member 808 can include a first end742 engaged with the membrane frame 806 and a second end 744 or a thirdend 746 in contact with a surface of a back side of the flexiblecontainer. Alternatively, the at least one column member 808 can beconfigured to externally support the membrane 804 and the membrane frame806 above any contents within the flexible container. In such anexample, the second end 744 or the third end 746 of the at least onecolumn member 808 can contact a surface external to the flexiblecontainer.

In the example shown, the at least one column member 808 can define aU-shape, with the curvature of the U-shape engaged with the membraneframe 806. The at least one column member 808 can be separate from orintegral with the membrane frame 806. In various examples, the at leastone column member 808 can be molded from a thermoplastic, such asacrylonitrile butadiene styrene (ABS), PVC or polypropylene or ametallic material.

FIGS. 9-11 illustrate sequential perspective views of a membrane 904,1004, 1104, a membrane frame 906, 1006, 1106 and at least one columnmember 908, 1008, 1108 subjected to a downward force F. As shown, the atleast one column member 908, 1008, 1108 can include a plurality ofcolumn members configured to change shape or position relative to themembrane frame 906, 1006, 1106 upon application of the downward force F.In an example, the plurality of column members 908, 1008, 1108 can bedeformed into a planar orientation with the membrane frame 906, 1006,1106, as shown in FIG. 11. Optionally, the at least one column member908, 1008, 1108 can include a recess that allows a portion of the columnmember to break-off upon application of the downward force F. Throughthe breaking-off of the portion of the column member, the membrane frame906, 1006, 1106 can contact a surface of a back side of a flexiblecontainer.

FIG. 12 illustrates an elevational view of a bottom portion 1216 of asystem 1200. The system 1200 can include a flexible container 1202, areconstitution port 1224 and an application port 1226. The flexiblecontainer 1202 can contain a freeze-dried material, such as freeze-driedbiological material. In an example, the freeze-dried biological materialis a blood plasma unit, which can include about 250-270 mL of bloodplasma from a single donor. The blood plasma unit, for example, can bedried so that its moisture content is below about 5% weight/weight(w/w), which can be stored, transported, and later reconstituted andapplied to a patient.

An advantage of a freeze-dried material is the possible storage for acomparably longer period of time at temperatures of about 0° C.(Celsius) up to room temperature and beyond, combined with a reducedweight due to reduced water content. Although a freeze-dried materialrequires reconstitution, the advantages are predominant in certainsituations, especially in emergency medicine under difficult treatmentconditions (e.g., in combat treating wounded warriors or in ambulancesand helicopters treating civilian trauma) when the thawing of frozenbiological material to be applied is time-consuming (e.g., around 15minutes or more) and inconvenient.

Freeze-dried biological material, for example, can be packaged forstorage in a container that presents a barrier to solvent vaportransmission, thereby minimizing the opportunity of rehydrating thedried contents. Advantageously, the flexible container 1202 can besealed 1251 (e.g., using heat sealing, RF welding or ultrasonic welding)near an end 1248 of the bottom portion 1216, which is located oppositethe reconstitution 1224 and application 1226 ports, after the driedcontents are entirely moved to the bottom portion 1216. The size andconfiguration of the bottom portion 1216 of the flexible container 1202can maintain the freeze-dried biological material prior to itsreconstitution in a moisture-free environment, thereby accommodatinglong-term storage (e.g., 2 to 3 years at refrigerated temperatures and aplurality of months at room temperature) and retaining its desiredqualities for transfusion.

In addition to storing the freeze-dried biological material, the bottomportion 1216 of the flexible container 1202 can be sized and configuredto receive reconstitution liquid, such as about 250 mL of water. In thisway, the bottom portion 1216 of the flexible container 1202 can providea single receptacle to store freeze-dried contents, rehydrate the driedcontents, and apply the rehydrated product to a patient.

The reconstitution 1224 and application 1226 ports can be thermally,ultrasonically, or adhesively coupled or RF welded to an outer perimeterof the second portion 1216 and oriented to be in fluid communicationwith an interior of the flexible container 1202 and its contents. Theports 1224, 1226 can include a diaphragm or other piercable membrane tomaintain material sterility and prevent inadvertent flow out of theflexible container 1202. To ensure that the material within the flexiblecontainer 1202 can easily and completely empty out of the container, atleast the application port 1226 can be positioned at a bottom end 1254of the second portion 1216, opposite the seal 1251, when the containeris suspended by a hang lumen 1252 located near the top end 1248.

Bar coding and tagging 1250 can be applied to the bottom portion 1216 ofthe flexible container 1202. The bar coding and tagging 1250 can, forexample, reflect biological material identification, including bloodplasma source, blood type, date of collection, etc., carried by thebottom portion 1216.

First aid is critical for the survival of a patient that has suffered aserious injury, such as a trauma victim. For example, initial treatmentof a severely wounded warrior in a combat situation can often mean thedifference between life and death. While it is necessary to treat woundsand stop the bleeding of a patient, it is also important to ensure thatthe patient's body is capable of properly functioning. Thus, it isnecessary to take steps to ensure that the patient's body is properlyhydrated after losing fluids due to the wounds. The present system andmethod address this issue.

Using existing technology, fluids within a patient are typicallyreplenished by intravenously delivering saline. While effective,research has indicated that delivery of blood plasma to the patient iseven more effective in replenishing fluid to the patient. Processing,storage, and delivery of the blood plasma can be critical to preventingcontamination of the plasma. An ideal way of delivering blood plasma isto store it in a freeze-dried form and reconstitute the blood plasma atthe time it is administered to the patient.

FIG. 13 illustrates a schematic view of reconstituting a freeze-driedbiological material, such as blood plasma. The freeze-dried biologicalmaterial can be stored in a bottom portion 1316 of a flexible container1302. This portion 1316 of the flexible container 1302 can be sized toreceive a reconstitution liquid (e.g., about 250 mL of water) through areconstitution port 1324 for mixing with the freeze-dried biologicalmaterial. In use, a needle or IV spike sized and configured to puncturea diaphragm or other piercable membrane within the reconstitution port1324 can be used to establish fluid communication between thereconstitution liquid and the freeze-dried biological material. Thefreeze-dried biological material and the reconstitution liquid can thenbe passed back and forth within the flexible container 1302 until adesired degree of mixing occurs, at which time the mixture is ready fortransfusion. More particularly, a caregiver can proceed to squeezeopposing ends or sides of the bottom portion 1316 of the flexiblecontainer 1302 to move and mix the freeze-dried biological material andthe reconstitution liquid.

FIG. 14 illustrates a schematic view of applying a reconstitutedbiological material, such as reconstituted blood plasma, to a patient.The reconstituted material can be administered by way of an applicationport 1326. An application set can include a phlebotomy needle 1456 forinsertion into a vein, aseptic tubing 1458 connecting the needle 1456 toa bottom portion 1416 of a flexible container 1402 and its reconstitutedbiological material contents, and a needle or IV spike to puncture adiaphragm or other piercable membrane within the application port 1326.

FIG. 15 illustrates a method 1500 of filling a flexible container with abiological material, such as blood plasma, freeze-drying the bloodplasma, and packaging the blood plasma for later use.

In operation 1502, a blood plasma source unit can be obtained. Bloodplasma can be obtained from a single donor or a pooling of donors bycollecting a unit of whole blood from the donor(s) in a closed systemcollection bag, followed by centrifugal separation of the blood plasmaand its collection in an integrally connected transfer bag. The bloodplasma can be obtained in individual units of about 270 mL, for example,shipped frozen and stored in a 20° C. freezer. Identificationinformation, maintained by bar coding or other tagging means, can besupplied with each individual donor blood plasma unit for traceabilitypurposes.

In operation 1504, the blood plasma source unit can be prepared forfreeze-drying. The blood plasma unit can be removed from the freezer andany associated packaging can be discarded. The blood plasma unit can betransferred into a plasma thawing unit and allowed to thaw. The thawedblood plasma unit can be bar code scanned, for example, and anidentification tag can be made. The identification tag can include unitspecific information to maintain traceability of the blood plasma.

In operation 1506, the blood plasma can be transferred into awater-impermeable, vapor-permeable, aseptic, sealable flexiblecontainer. The flexible container and the blood plasma source unit canbe coupled together using a material entry port in the form of aseptictubing. The blood plasma can be transferred through the aseptic tubingusing positive pressure. The total mass of the transferred blood plasmacan be about 270 g. Once the blood plasma has been transferred, aportion of the aseptic tubing can be thermally or otherwise sealed toprotect the unit from contamination.

The flexible container can include a first side incorporating a membraneand a second side, which are spaced from one another by a membrane frameand at least one column member. The identification tag made in operation1504 can be attached to the flexible container.

In operation 1508, the filled flexible container can be placed on ahorizontally-oriented freeze-dryer tray such that the membrane is ontop, facing upward, and the container can be freeze-dried. Thisplacement of the membrane can allow for controlled and consistentconduction during the freeze-drying process, as air or solvent vapor canescape the flexible container through the membrane. Optionally, thefilled flexible container can be placed on a vertically-orientedfreeze-dryer tray and the membrane can be incorporated at any locationof an upper, first portion of the container. After placing the flexiblecontainer on a shelf in a freeze-dryer chamber, the shelf can be cooledusing a heating and cooling unit to preliminarily freeze the article tobe freeze-dried. Alternatively, the filled flexible container to befreeze-dried can be pre-frozen using a separate unit (e.g., a −60° C.freezer) and arranged on the shelf.

Next, the pressure inside the freeze-dryer can be reduced to sublimationdry the contents of the flexible container. The pressure inside thefreeze-dryer can be reduced to about 100 mTorr to sublimate ice tosolvent vapor without going through a liquid state. During thesublimation drying step, the shelf within the freeze-dryer chamber canbe maintained at an adequate temperature for supplying a latent heat ofsublimation using the heating and cooling unit.

Solvent vapor released from the contents of the flexible container bysublimation can be captured by a cold trap or other type of capturingunit. In the case of using a cold trap (condenser unit), the cold trapcan be cooled to a temperature below the temperature of the contents,and preferably to a temperature that demonstrates a solvent vaporpressure sufficiently lower than the solvent vapor pressure of water atthe temperature of the contents (for example, −50 to −60° C.).

In an example, the freeze-drying cycle can include cooling the shelf toless than about −40° C., loading the filled flexible container and itstray onto the shelf, initiating a six or seven day freeze-drying cycleincluding a four or five day primary drying cycle and a two daysecondary drying cycle, ending the secondary drying cycle and breakvacuuming using extra dry, high purity carbon dioxide, removing thefreeze-dried filled flexible container and placing it in a desiccatedstorage chamber.

In operation 1510, the freeze-dried blood plasma can be moved to aportion of the flexible container spaced from the membrane, the membraneframe, and the at least one column member and then sealed. Specifically,the flexible container can be removed from the desiccated storagechamber and its freeze-dried blood plasma contents can be moved to aportion of the flexible container including two ports-a reconstitutionport and an application port. Prior to making a seal of about 1 inch,for example, across a midline of the flexible container, for example, adownward force can be applied to the membrane frame to cause the atleast one column member to collapse. A portion of the seal can be cutthrough and a first portion of the flexible container, which includesthe membrane, the membrane frame and the at least one column member, canbe discarded in a biohazard container. A hang lumen can be added to theremaining portion of the formed seal.

In operation 1512, the remaining portion of the formed seal canoptionally be cleaned. In an example, the non-discarded second portionof the flexible container can be inverted such that the seal, positionedopposite the reconstitution and application ports, can be immersed into10% bleach or another cleansing solution. This cleansing can ensure thatno blood plasma is on a surface of the seal. After the seal is allowedto soak for about 10 minutes, the second portion of the flexiblecontainer can be rinsed with deionized water.

In operation 1514, the second portion of the flexible container can belabeled and packaged. The bar code printed on the identification tag inoperation 1504 can be scanned and three labels with associatedinformation can be printed. The three labels can be placed on the secondportion of the flexible container, which includes the freeze-driedplasma, an external foil containment pouch and a final packaging. Afirst label can be placed on the second portion of the flexiblecontainer and the original identification tag can be removed. Thelabeled second portion of the flexible container can then be placed intothe external foil containment pouch and packaged. The second portion ofthe flexible container can be packaged in a military grade ruggedizedcontainer with 250 mL of reconstitution liquid, for example, and aseptictubing for transferring the reconstitution liquid to the flexiblecontainer.

CLOSING NOTES

Existing systems and methods for freeze-drying, repackaging and usingfreeze-dried contents suffer from concerns of contamination, expense andlack of convenience. Advantageously, the present subject matter providesan economical and efficient system and method for protecting materialfrom contamination through the steps of filling, freeze-drying,packaging, storing and use. The system and method can be designed forblood products, such as blood plasma, and can be adoptable to othermaterials that would benefit from the design and features of theinvention.

The above Detailed Description includes references to the accompanyingdrawings, which form a part of the Detailed Description. The DetailedDescription should be read with reference to the drawings. The drawingsshow, by way of illustration, specific embodiments in which the presentsystem and method can be practiced. These embodiments are also referredto herein as “examples.” While certain examples are described withrespect a blood plasma biological material, it is to be appreciated thatthe present disclosure is equally applicable to non-blood relatedbiological materials, as well as non-biological materials.

The above Detailed Description is intended to be illustrative, and notrestrictive. For example, the above-described examples (or one or morefeatures or components thereof) can be used in combination with eachother. Other embodiments can be used, such as by one of ordinary skillin the art upon reviewing the above Detailed Description. Also, variousfeatures or components can be grouped together to streamline thedisclosure. This should not be interpreted as intending that anunclaimed disclosed feature is essential to any claim. Rather, inventivesubject matter can lie in less than all features of a particulardisclosed embodiment. Thus, the following claims are hereby incorporatedinto the Detailed Description, with each claim standing on its own as aseparate embodiment. The scope of the invention should be determinedwith reference to the appended claims, along with the full scope ofequivalents to which such claims are entitled.

Certain terms are used throughout this patent document to refer toparticular features or components. As one skilled in the art willappreciate, different persons may refer to the same feature or componentby different names. This patent document does not intend to distinguishbetween components or features that differ in name but not in function.

For the following defined terms, certain definitions shall be applied,unless a different definition is given elsewhere in this patentdocument. The terms “a.” “an,” and “the” are used to include one or morethan one, independent of any other instances or usages of “at least one”or “one or more.” The term “or” is used to refer to a nonexclusive or,such that “A or B” includes “A but not B,” “B but not A,” and “A and B.”All numeric values are assumed to be modified by the term “about,”whether or not explicitly indicated. The term “about” generally refersto a range of numbers that one of skill in the art would considerequivalent to the recited value (e.g., having the same function orresult). In many instances, the term “about” can include numbers thatare rounded to the nearest significant figure. The recitation ofnumerical ranges by endpoints includes all numbers and sub-ranges withinthat range (e.g., 1 to 4 includes 1, 1.5, 1.75, 2, 2.3, 2.6, 2.9, etc.and 1 to 1.5, 1 to 2, 1 to 3, 2 to 3.5, 2 to 4, 3 to 4, 3 to 4.25,etc.). The term “patient” is intended to include mammals, such as forhuman or veterinary applications.

In the appended claims, the terms “including” and “in which” are used asthe plain-English equivalents of the respective terms “comprising” and“wherein.” Also, in the following claims, the terms “including” and“comprising” are open-ended, that is, a system, kit, or method thatincludes features or components in addition to those listed after such aterm in a claim are still deemed to fall within the scope of that claim.Moreover, in the following claims, the terms “first.” “second,” and“third,” etc. are used merely as labels, and are not intended to imposenumerical requirements on their objects.

The Abstract is provided to allow the reader to quickly ascertain thenature of the technical disclosure. It is submitted with theunderstanding that it will not be used to interpret or limit the scopeor meaning of the claims.

What is claimed is:
 1. A freeze-drying system, comprising: a containerhaving a first portion and a second portion, the first portion and thesecond portion each comprising at least one gas-impermeable surface,each configured to contain a substance that can be passed from withinthe first portion to within the second portion, and each separable fromthe other; a gas-permeable membrane integrated into at least onegas-impermeable surface of the first portion, the gas-permeable membraneconfigured to transmit air or solvent vapor out of, and resist liquid orcontaminant passage into, the container; and at least one port to allowfor an introduction or a withdrawal of the substance into or out of thecontainer.
 2. The freeze-drying system of claim 1, wherein the at leastone port includes at east one port in each of the first portion and thesecond portion.
 3. The freeze-drying system of claim 2, wherein the atleast one port in the first portion allows for the introduction of asubstance into the container.
 4. The freeze-drying system of claim 2,wherein the at least one port in the second portion is a reconstitutionport that allows for the introduction of a substance into the containeror an application port that allows for the withdrawal of a substance outof the container.
 5. The freeze-drying system of claim 1, wherein thegas-permeable membrane includes a material selected from a porouspolymer, a woven polymeric fabric, a non-woven polymeric fabric, glassfiber, or cellulose.
 6. The freeze-drying system of claim 5, wherein thegas-permeable membrane includes a porous polymer material comprisingpolytetrafluoroethylene.
 7. The freeze-drying system of claim 1, furthercomprising a removable cover protecting the gas-permeable membrane. 8.The freeze-drying system of claim 1, further comprising a substancecomprising a biological material.
 9. The freeze-drying system of claim1, further comprising a substance comprising a non-biological material.10. The freeze-drying system of claim 1, further comprising a supportconfigured to maintain the gas-permeable membrane at a spaced distancefrom any substance received within the first portion.
 11. Thefreeze-drying system of claim 1, further comprising a frame within thefirst portion, the frame coupled to a perimeter of the gas-permeablemembrane.
 12. The freeze-drying system of claim 11, further comprisingat least one support member engaged with the frame and configured tosupport the frame a spaced distance from any substance received withinthe first portion.
 13. The freeze-drying system of claim 12, wherein theat least one support member is integral with the frame.
 14. Thefreeze-drying system of claim 12, wherein the at least one supportmember defines a U-shape, with the curvature of the U-shape engaged withthe frame.
 15. The freeze-drying system of claim 11, further comprisingone or more magnetic or hook members coupled to or integrated with thefirst portion, the gas-permeable membrane, or the frame and configuredto interact with an external magnetic member or an external support tomaintain the gas-permeable membrane a spaced distance from any substancereceived within the first portion.
 16. A system for freeze-drying andpackaging, comprising: a gas-impermeable container including at a firstportion and a second portion, each configured to contain aheat-sensitive substance that can be passed from within the firstportion to within the second portion; a gas-permeable membraneintegrated into a surface of the first portion, the membrane configuredto transmit air or solvent vapor out of, and resist liquid orcontaminant passage into, the gas-impermeable container; at least oneport in fluid communication with an interior of the container to allowfor an introduction or a withdrawal of a substance into or out of thecontainer; and the heat-sensitive substance.
 17. The system of claim 16,wherein the gas-permeable membrane includes a material selected from aporous polymer, a woven polymeric fabric, a non-woven polymeric fabric,glass fiber, or cellulose.
 18. The system of claim 16, furthercomprising a removable cover protecting the gas-permeable membrane. 19.The system of claim 18, the removable cover further comprising a tabthat extends beyond a perimeter of the gas-permeable membrane to allow auser to grasp and remove the cover to expose the membrane.
 20. Thesystem of claim 16, further comprising a frame supporting thegas-permeable membrane.